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Failure of viral oncoproteins to target the p53-homologue p51A
Judith Roth1, Matthias Dobbelstein2
1Gastroenterologie und Stoffwechsel, Zentrum Innere Medizin, Klinikum der Universität Marburg, Baldingerstraße, 35043 Marburg, Germany1.
Abstract:
The p51/p63/KET proteins were identified based on their strong homology to the tumour suppressor p53 and a related set of proteins termed p73. All these protein species were shown to activate transcription from at least some p53-responsive promoters. To evaluate a possible role of the transcriptionally active splicing variant p51A/p63gamma in tumour suppression, we determined whether viral oncoproteins that inactivate p53 might also target p51A. Neither the large T-antigen of simian vacuolating virus 40 (SV40) nor the E6 protein from human papillomavirus type 18 were found to inhibit p51A-mediated transcription, whereas they strongly suppress the activity of p53. Further, SV40 T-antigen directly interacts with p53 but not detectably with p51A. Finally, a cytoplasmic mutant (K128A) of SV40 T-antigen relocalizes p53 from the nucleus to the cytoplasm, but p51A remains in the nucleus when coexpressed with cytoplasmic T-antigen. These results strongly suggest that the inhibitory effect of these viral oncoproteins is specific for p53 and does not measurably affect p51A. Thus, unlike p53, p51A does not appear to be a necessary target in virus-induced cell transformation and may not exert a role comparable to p53 in tumour suppression.
Insights
Viral oncoproteins inactivate tumor suppressor p53 but not the related p51A protein. This suggests p51A may not play a significant role in tumor suppression or virus-induced cell transformation.
Area of Science:
- Molecular Biology
- Oncology
- Virology
Background:
- p53 is a critical tumor suppressor.
- p63/p73 family proteins share homology with p53.
- p51A is a transcriptionally active splicing variant of p63.
Purpose of the Study:
- To investigate if viral oncoproteins targeting p53 also affect p51A.
- To evaluate the potential tumor suppressor role of p51A.
Main Methods:
- Assessed inhibition of p51A-mediated transcription by SV40 T-antigen and HPV18 E6.
- Examined direct interaction between SV40 T-antigen and p53/p51A.
- Analyzed subcellular localization of p53 and p51A with a cytoplasmic SV40 T-antigen mutant.
Main Results:
- SV40 T-antigen and HPV18 E6 inhibited p53 activity but not p51A activity.
- SV40 T-antigen directly interacted with p53, but not p51A.
- Cytoplasmic SV40 T-antigen relocalized p53, but p51A remained nuclear.
Conclusions:
- Viral oncoprotein inhibition is specific to p53, not p51A.
- p51A does not appear to be a necessary target for viral oncoproteins in cell transformation.
- p51A may not have a tumor suppressor role comparable to p53.